title: Sesquiterpene lactones downregulate G2/M cell cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells.
abstract: Soft tissue sarcomas (STS) represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential. Many studies have demonstrated the great potential of plant-derived agents in the treatment of various malignant entities. The present study investigates the effects of the sesquiterpene lactones costunolide and dehydrocostus lactone on cell cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner. Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27(Kip1). In addition, accumulation of cells at the G2/M phase transition interface resulted in a significant decrease in cdc2 (CDK1) together with cyclin B1. Costunolide had no effect on the cell cycle. Based on the fact that STS tend to form daughter cell nests and metastasize, the expression levels of matrix metalloproteinases (MMPs), which play a crucial role in extracellular matrix degradation and metastasis, were investigated by Luminex® technology and real-time RT-PCR. In the presence of costunolide, MMP-2 and -9 levels were significantly increased in SW-982 and TE-671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and -9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlock™ insert system.
authors.affiliation: Department of Orthopedic Surgery, Medical University of Graz, Graz, Austria. birgit.lohberger@medunigraz.at
authors.forename: Birgit
authors.initials: B
authors.lastname: Lohberger
authors.forename: Beate
authors.initials: B
authors.lastname: Rinner
authors.forename: Nicole
authors.initials: N
authors.lastname: Stuendl
authors.forename: Heike
authors.initials: H
authors.lastname: Kaltenegger
authors.forename: Bibiane
authors.initials: B
authors.lastname: Steinecker-Frohnwieser
authors.forename: Eva
authors.initials: E
authors.lastname: Bernhart
authors.forename: Ehsan
authors.initials: E
authors.lastname: Bonyadi Rad
authors.forename: Annelie Martina
authors.initials: AM
authors.lastname: Weinberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Leithner
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Nadine
authors.initials: N
authors.lastname: Kretschmer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D012509:Sarcoma / Q000473:pathology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D012717:Sesquiterpenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; C083030:dehydrocostus lactone; C002602:costunolide; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D017364:Collagenases